Proactive Metabolite Testing in Patients on Thiopurine May Yield Long-Term Clinical Benefits in Inflammatory Bowel Disease.

BACKGROUND: The thiopurine medications are well established in the treatment of inflammatory bowel disease (IBD). There is significant variation in levels of toxic and therapeutic metabolites. Current data from small or short-term studies support therapeutic drug monitoring (TDM) in assessing azathioprine (AZA) and 6-mercaptopurine (6MP). TDM of thiopurines involves measurement and interpretation of metabolites 6-TGN and 6-MMPR. AIMS: This study aimed to assess long-cterm outcomes of patients on thiopurines following therapeutic drug monitoring. METHODS: A multicenter retrospective observational study of outcomes post thiopurine TDM was conducted. Demographics, disease characteristics, physician global assessment, IBD therapy at baseline TDM and again at 12 months were collected. Clinical outcomes were analyzed according to TDM result, and indication for TDM including proactive and other indications. RESULTS: The study included 541 patients. Only 39% of patients had appropriate dosing of thiopurines. AZA/6MP TDM informed a management change in 61.9%, and enabled 88.8% of the cohort to continue AZA/6MP following TDM. At 12 months following TDM the majority (74.1%) of the cohort remained on AZA/6MP. Clinical remission was higher at 12-months following thiopurines TDM (68%) compared to baseline (37%), including proactive TDM. Post TDM, 13.0% of patients were identified as shunters and commenced on thiopurine-allopurinol co-therapy. CONCLUSION: Thiopurine TDM resulted in a change in management for the majority of patients. Post TDM significantly more patients were in remission. TDM allowed the identification of non-adherence and shunters who, without intervention, would not reach therapeutic drug levels. Proactive TDM allowed identification and management of inappropriate dosing, and was associated with increased levels of clinical remission.

Analysis of mono-, di-, and triphosphates of thioguanosine and methylthioinosine in children with acute lymphoblastic leukemia by LC-MS/MS.

Mercaptopurine (6-MP) is an indispensable, first-line, drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, 6-MP has several intrinsic drawbacks, such as large individual variability in the drug response, undesirable adverse reactions, and drug resistance in patients with release ALL, which requires therapeutic drug monitoring (TDM). Several studies analyzed the total concentration of thiopurine nucleotides in red blood cells (RBCs) after hydrolysis, and two studies detected them separately and accurately by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, we developed a rapid and robust LC-MS/MS method for simultaneous quantitation of mono-, di-, and triphosphates of thioguanosine and methylthioinosine. Not only EDTA and DTT were added, but also EHT1864, a new Rac family small GTPases inhibitor, was innovatively added to ensure the stability of the analytes. Commercial availability and relatively low cost compound methotrexate-D3 was selected as internal standards. The linearity, accuracy, precision, recovery, matrix effect and stability of the method were all in line with the guidelines. This method provide an accurate and robust new solution for the determination of 6 metabolites of MP in RBCs from ALL patients with maintenance therapy.

Health-related quality of life of youth with inflammatory bowel disease: a comparison with published data using the PedsQL 4.0 generic core scales.

BACKGROUND: This study compared youth and parent-proxy reports of health-related quality of life (HRQoL) among youth with inflammatory bowel disease (IBD) to published comparison group data and examined concordance between youth and parent-proxy reports of HRQoL. METHODS: One hundred thirty-six youth and parent-proxy reports on the PedsQL 4.0 Generic Core Scales were compared to published data from chronically ill, acutely ill, and healthy comparison groups using independent samples t-tests. Reporter agreement was examined using paired samples t-tests and intraclass correlations (ICCs). RESULTS: Youth with IBD reported lower psychosocial functioning than the healthy comparison group, higher physical and social functioning than the chronically ill group, and lower school functioning than all published comparison groups. Parent-proxy reports of youth HRQoL were higher than the chronically ill group, but lower than the healthy group on all scales except psychosocial functioning. Youth with active IBD reported lower physical health domain scores than youth with inactive disease. Concordance between youth and parent-proxy reports was moderate, with the lowest agreement in school and social functioning. CONCLUSIONS: Youth with IBD and their parents rate HRQoL as lower than healthy youth but do not perceive the impact of IBD to be as limiting as in other chronic conditions. Youth report suggests that IBD may be particularly detrimental to HRQoL in the school functioning domain. Moderate agreement between parent and youth reports substantiates continued use of multiple informants in studies of pediatric HRQoL.

Evaluación del ribósido de alpurinol contra la leishmaniasis cutánea ecuatoriana / Evaluation of allopurinol-riboside therapy against Ecuatorian cutaneous leishmaniasis

Se realizó un randomizado de 75 pacientes con leishmaniasis cutánea ecuatoriano con el fin de determinar el índice terapéutico de una nueva droga oral antileishmania, el ribósido de alopurinol más probenecid. Este agente fue evaluado comparándolo con controles positivos que se trataron con pentostam y con testigos no tratados. Las medidas de las lesiones disminuyeron rápidamente durante la terapia, lo que permitió determinar el porcentaje de cicatrización en los diferentes grupos. En el día 70 se realizó la evaluación de la curación de los pacientes en los diferentes grupos, obteniéndose: alopurinol (1.500 mg/6 h) más probenecid (500 mg/6 h) por 28 días, dió una curación con lesiones cicatrizadas en 10 (45,5 por ciento) de los 22 pacientes. Con pentostam (20 mg Sb/kg/día, IM por 20 días) se obtuvo una curación en 28 pacientes siendo esto de 100 por ciento de cicatrización. El grupo de no tratamiento presentó un porcentaje muy elevado de curación espontánea en 9 (75,0 por ciento) de los 12 pacientes. Todos los pacientes con tratamiento fallido o recidivas recibieron posteriormente tratamiento con pentostam. Este estudio sugiere que le ribósido de alopurinol más probenecid no es una droga con mayor eficacia contra la leishmaniasis cutánea ecuatoriana

Inhibition of the synthesis of glycoproteins and induction of the differentiation of HL-60 promyelocytic leukemia cells by 6-methylmercaptopurine ribonucleoside.

HL-60 promyelocytic leukemia cells were induced to differentiate along the granulocytic pathway by exposure to 6-methylmercaptopurine ribonucleoside (6-MMPR). The interference with cellular replication and the induction of terminal maturation by 6-MMPR appeared to be a consequence of the inhibition of purine nucleotide biosynthesis de novo, since the simultaneous exposure of HL-60 cells to 6-MMPR and adenine completely prevented cellular differentiation, as measured by both nitro-blue tetrazolium reduction and the phagocytosis of latex beads, and partially prevented growth inhibition. The induction of HL-60 leukemia cell maturation by 6-MMPR was preceded by a marked reduction in the incorporation of [3H]mannose into glycoproteins and into the dolichol-oligosaccharide precursors of N-linked glycoprotein biosynthesis. Simultaneous exposure of HL-60 cells to 6-MMPR and adenine completely prevented the reduction in [3H]mannose incorporation into glycoproteins produced by the purine nucleoside antimetabolite. These findings suggest that the utilization of mannose for glycoprotein biosynthesis may be a component of the mechanism by which 6-MMPR causes the induction of the terminal differentiation of HL-60 leukemia cells.

Behçet's disease: a case with hemoptysis, pseudotumor cerbri, and arteritis.

A case of Behçet's diease with massive hemoptyis is described. The hemoptysis occurred during disease exacerbation with extensive oropharyngeal and laryngeal ulcerations, and responded to high-dose corticosteroid therapy. Other unusual manifestations included a light sensitive dermatitis, pseudotumor cerebri, and right bundle branch block. Also, arteritis and subsequent occlusion of the femoral and popliteal arteries occurred. Although uncommon, pumonary involvement may be life-threatening and should be treated with corticosteroids. Both pulmonary and neurologic involvement tend to occur with active aphthosis and respond to corticosteroids. This case underscores the protean nature of the organ system involvement in Behçet's disease and supports the concept that vasculitis is a primary pathophysiologic event.

Feedback inhibition by 6-methylthioinosine 3',5'-cyclic monophosphate in tumor cells resistant to the nucleoside.

The 3',5'-cyclic phosphate derivative (cMTIMP) of methylthioinosine (MTI) was shown to produce feedback inhibition of the de novo purine pathway in an Ehrlich ascites tumor subline resistant to MTI because of lack of adenosine kinase activity for the nucleoside analog.